Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38 |
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| Authors: | Bai Xiaochun Ma Dongzhu Liu Anling Shen Xiaoyun Wang Qiming J Liu Yongjian Jiang Yu |
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| Institution: | Department of Pharmacology, University of Pittsburgh School of Medicine, E1357 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA. |
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| Abstract: | The mammalian target of rapamycin, mTOR, is a central regulator of cell growth. Its activity is regulated by Rheb, a Ras-like small guanosine triphosphatase (GTPase), in response to growth factor stimulation and nutrient availability. We show that Rheb regulates mTOR through FKBP38, a member of the FK506-binding protein (FKBP) family that is structurally related to FKBP12. FKBP38 binds to mTOR and inhibits its activity in a manner similar to that of the FKBP12-rapamycin complex. Rheb interacts directly with FKBP38 and prevents its association with mTOR in a guanosine 5'-triphosphate (GTP)-dependent manner. Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability. |
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